A physiologically based kinetic model for elucidating the in vivo distribution of administered mesenchymal stem cells

Although mesenchymal stem cells (MSCs) present a promising tool in cell therapy for the treatment of various diseases, the in vivo distribution of administered MSCs has still been poorly understood, which hampers the precise prediction and evaluation of their therapeutic efficacy. Here, we developed the first model to characterize the physiological kinetics of administered MSCs based on direct visualization of cell spatiotemporal disposition by intravital microscopy and assessment of cell quantity using flow cytometry. This physiologically based kinetic model was validated with multiple external datasets, indicating potential inter-route and inter-species predictive capability. Our results suggest that the targeting efficiency of MSCs is determined by the lung retention and interaction between MSCs and target organs, including cell arrest, depletion and release. By adapting specific parameters, this model can be easily applied to abnormal conditions or other types of circulating cells for designing treatment protocols and guiding future experiments

Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31